5-(1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-D]pyrimidine derivatives

ABSTRACT

Compounds of the formula (I), in which R 1 , R 2 , R 2a  and R 3  have the meanings indicated in Claim  1 , are inhibitors of PDK1 and cell proliferation/cell vitality and can be employed for the treatment of tumors.

The invention relates to compounds of the formula I

in which

-   R¹ denotes A, —C(R³)(R⁴)—Ar, —C(R³)(R⁴)-Het or —C(R³)(R⁴)-Cyc,-   R², R^(2a) each, independently of one another, denote H, A, Hal, CN,    —[C(R³)₂]_(n)—Ar′, —[C(R³)₂]_(n)-Het′, —[C(R³)₂]_(n)-Cyc, OR³ or    N(R³)₂,-   R³ denotes H or A,-   R⁴ denotes H, A, —[C(R³)₂]_(m)OR³, —[C(R³)₂]_(m)N(R³)₂ or    —[C(R³)₂]_(m)Het¹,-   A denotes unbranched or branched alkyl having 1-6C atoms, in which    one or two non-adjacent CH₂ groups may be replaced by O, N and/or S    atoms and/or by —CH═CH— groups and/or, in addition, 1-7H atoms may    be replaced by F,-   Cyc denotes cycloalkyl having 3, 4, 5, 6 or 7C atoms,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂,    NR³COA, NR³SO₂A, COR³, SO₂N(R³)₂ and/or S(O)_(n)A,-   Ar′ denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OR³, N(R³)₂, SR³, NO₂, CN, COOR³,    CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A, CO-Het¹, Het¹,    [C(R³)₂]_(n)—N(R³)₂, [C(R³)₂]_(n)Het¹, O[C(R³)₂]_(n)N(R³)₂,    O[C(R³)₂]_(n)Het¹, NHCOOA, NHCON(R³)₂, NHCOO[C(R³)₂]_(n)N(R³)₂,    NHCOO[C(R³)₂]_(n)Het¹, NHCONH[C(R³)₂]_(n)N(R³)₂,    NHCONH[C(R³)₂]_(n)Het¹, OCONH[C(R³)₂]_(n)N(R³)₂,    OCONH[C(R³)₂]_(n)Het¹, CO-Het¹, CHO and/or COA,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, and/or O and/or S atoms which is    unsubstituted or mono- or disubstituted by Hal, A, OR³, N(R³)₂, NO₂,    CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A, COR³, SO₂NR³ and/or S(O)_(n)A,-   Het′ denotes a mono-, bi- or tricyclic saturated, unsaturated or    aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is    unsubstituted or may be mono- or disubstituted by Hal, A, OR³,    N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂,    S(O)_(m)A, CO-Het¹, Het¹, [C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)Het¹,    O[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹, NHCOOA, NHCON(R³)₂,    NHCOO[C(R³)₂]_(n)N(R³)₂, NHCOO[C(R³)₂]_(n)Het¹,    NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]_(n)Het¹,    OCONH[C(R³)₂]_(n)N(R³)₂, OCONH[C(R³)₂]_(n-)Het¹, CO-Het¹, CHO, COA,    ═S, ═NH, ═NA and/or ═O (carbonyl oxygen),-   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N    and/or O atoms, which may be mono- or disubstituted by A, OA, OH,    Hal and/or ═O (carbonyl oxygen),-   Hal denotes F, Cl, Br or I-   n denotes 0, 1 or 2-   m denotes 1 or 2,    and pharmaceutically usable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The compounds of the formula I according to the invention also includethe pharmaceutically usable derivatives and solvates thereof.

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

It has been found that the compounds of the formula I and salts and/orsolvates thereof have very valuable pharmacological properties whilebeing well tolerated.

In particular, they exhibit a cell proliferation/cellvitality-inhibiting action as antagonists or agonists. The compoundsaccording to the invention can therefore be used for the combatingand/or treatment of tumours, tumour growth and/or tumour metastases.

The antiproliferative action can be tested in a proliferationassay/vitality assay.

The compounds according to the invention inhibit the proliferation ofcancer cells, for example the proliferation of cell lines A2780 andHCT116.

3-(1,2,3-Triazol-4-yl)pyrrolo[2,3-b]pyridine derivatives are describedas PDK1 inhibitors in WO 2010/127754 A1.

Accordingly, the compounds according to the invention or apharmaceutically acceptable salt thereof are administered for thetreatment of cancer, including solid carcinomas, such as, for example,carcinomas (for example of the lungs, pancreas, thyroid, bladder orcolon), myeloid diseases (for example myeloid leukaemia) or adenomas(for example villous colon adenoma).

The tumours furthermore include monocytic leukaemia, brain, urogenital,lymphatic system, stomach, laryngeal and lung carcinoma, including lungadenocarcinoma and small-cell lung carcinoma, pancreatic and/or breastcarcinoma.

The compounds are furthermore useful in the treatment of immunedeficiency induced by HIV-1 (Human Immunodeficiency Virus Type 1).

Cancer-like hyperproliferative diseases are to be regarded as braincancer, lung cancer, squamous epithelial cancer, bladder cancer, stomachcancer, pancreatic cancer, liver cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphomas, chronic leukaemia andacute leukaemia. In particular, cancer-like cell growth is a diseasewhich represents a target of the present invention. The presentinvention therefore relates to compounds according to the invention asmedicaments and/or medicament active compounds in the treatment and/orprophylaxis of the said diseases and to the use of compounds accordingto the invention for the preparation of a pharmaceutical for thetreatment and/or prophylaxis of the said diseases and to a process forthe treatment of the said diseases comprising the administration of oneor more compounds according to the invention to a patient in need ofsuch an administration.

It can be shown that the compounds according to the invention have anantiproliferative action. The compounds according to the invention areadministered to a patient having a hyperproliferative disease, forexample to inhibit tumour growth, to reduce inflammation associated witha lymphoproliferative disease, to inhibit transplant rejection orneurological damage due to tissue repair, etc. The present compounds aresuitable for prophylactic or therapeutic purposes. As used herein, theterm “treatment” is used to refer to both the prevention of diseases andthe treatment of pre-existing conditions. The prevention ofproliferation/vitality is achieved by administration of the compoundsaccording to the invention prior to the development of overt disease,for example for preventing tumour growth. Alternatively, the compoundsare used for the treatment of ongoing diseases by stabilising orimproving the clinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of a human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro testing.Typically, a culture of the cell is incubated with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitcell proliferation, cell vitality or migration, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from a biopsy sample. The amount of cells remainingafter the treatment are then determined.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue, while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

There are many diseases associated with deregulation of cellproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, perianastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

The compounds of the formula I, also act as regulators, modulators orinhibitors of protein kinases, in particular of the serine/threoninekinase type, which include, inter alia, phosphoinositide-dependentkinase 1 (PDK1). The compounds according to the invention exhibit acertain action in the inhibition of the serine/threonine kinases PDK1,IKK and TBK1.

PDK1 phosphorylates and activates a sub-group of the AGC protein kinasefamily, comprising PKB, SGK, S6K and PKC isoforms. These kinases areinvolved in the PI3K signal transduction pathway and control basiccellular functions, such as survival, growth and differentiation. PDK1is thus an important regulator of diverse metabolic, proliferative andlife-sustaining effects.

WO 2008/079988 A2 describes quinazoline derivatives as PDK1 inhibitorsfor combating cancer.

WO 2008/112217 A1 describes benzonaphthyridine derivatives as PDK1inhibitors for combating cancer.

Pyridinonyl derivatives are known as PDK1 inhibitors for combatingcancer from WO 2008/005457.

Pyrrolopyridine kinase modulators for combating cancer are described inWO WO 2008/124849.

WO 2006/106326 A1 and WO 2008/156726 A1 describe other heterocycliccompounds as PDK1 inhibitors for combating cancer.

WO 2009/054941 A1 describes pyrrolopyridine derivatives as PDK1inhibitors for combating cancer.

IKKε and TBK1 are serine/threonine kinases which are highly homologousto one another and to other IkB kinases. The two kinases play anintegral role in the innate immune system. Double-stranded RNA virusesare recognised by the Toll-like receptors 3 and 4 and the RNA helicasesRIG-I and MDA-5 and result in activation of the TRIF-TBK1/IKKε-IRF3signalling cascade, which results in a type I interferon response.

In 2007, Boehm et al. described IKKε as a novel breast cancer oncogene[J. S. Boehm et al., Cell 129, 1065-1079, 2007]. 354 kinases wereinvestigated with respect to their ability to recapitulate theRas-transforming phenotype together with an activated form of the MAPKkinase Mek. IKKε was identified here as a cooperative oncogene.

In addition, the authors were able to show that IKBKE is amplified andoverexpressed in numerous breast cancer cell lines and tumour samples.The reduction in gene expression by means of RNA interference in breastcancer cells induces apoptosis and impairs the proliferation thereof.Eddy et al. obtained similar findings in 2005, which underlines theimportance of IKKε in breast cancer diseases [S. F. Eddy et al., CancerRes. 2005; 65 (24), 11375-11383].

A protumorigenic effect of TBK1 was reported for the first time in 2006.In a screening of a gene library comprising 251,000 cDNA, Korherr et al.identified precisely three genes, TRIF, TBK1 and IRF3, which aretypically involved in the innate immune defence as proangiogenic factors[C. Korherr et al., PNAS, 103, 4240-4245, 2006]. In 2006, Chien et al.[Y. Chien et al., Cell 127, 157-170, 2006] published that TBK1−/− cellscan only be transformed to a limited extent using oncogenic Ras, whichsuggests an involvement of TBK1 in the Ras-mediated transformation.Furthermore, they were able to show that an RNAi-mediated knockdown ofTBK1 triggers apoptosis in MCF-7 and Panc-1 cells. Barbie et al.recently published that TBK1 is of essential importance in numerouscancer cell lines with mutated K-Ras, which suggests that TBK1intervention could be of therapeutic importance in corresponding tumours[D. A. Barbie et al., Nature Letters 1-5, 2009].

Diseases caused by protein kinases are characterised by anomalousactivity or hyperactivity of such protein kinases. Anomalous activityrelates to either: (1) expression in cells which do not usually expressthese protein kinases; (2) increased kinase expression, which results inundesired cell proliferation, such as cancer; (3) increased kinaseactivity, which results in undesired cell proliferation, such as cancer,and/or in hyperactivity of the corresponding protein kinases.Hyperactivity relates either to amplification of the gene which encodesfor a certain protein kinase, or the generation of an activity levelwhich can be correlated with a cell proliferation disease (i.e. theseverity of one or more symptoms of the cell proliferation diseaseincreases with increasing kinase level). The bioavailability of aprotein kinase may also be influenced by the presence or absence of aset of binding proteins of this kinase.

The most important types of cancer that can be treated using a compoundaccording to the invention include colorectal cancer, small-cell lungcancer, non-small-cell lung cancer, multiple myeloma as well as renalcell carcinoma and endometrium carcinoma, particularly also types ofcancer in which PTEN is mutated, inter alia breast cancer, prostatecancer and glioblastoma.

In addition, the compounds according to the invention can be used toachieve additive or synergistic effects in certain existing cancerchemotherapies and radiotherapies and/or to restore the efficacy ofcertain existing cancer chemotherapies and radiotherapies.

Compounds of the formula I are also taken to mean the hydrates andsolvates of these compounds, furthermore pharmaceutically usablederivatives.

The invention also relates to the optically active forms(stereoisomers), salts, the enantiomers, the racemates, thediastereomers and the hydrates and solvates of these compounds. Solvateof the compounds are taken to mean adductions of inert solvent moleculesonto the compounds which form owing to their mutual attractive force.Solvate are, for example, mono- or dihydrates or alcoholates. Compoundsof the formula I are of course also taken to mean the solvates of thesalts of the compounds according to the invention.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds. Prodrug derivatives are taken to mean compounds ofthe formula I which have been modified by means of, for example, alkylor acyl groups, sugars or oligopeptides and which are rapidly cleaved inthe organism to form the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active compound which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, condition or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable salts, tautomers and stereoisomersthereof, characterised in that the indole-protecting group is cleavedoff from a compound of the formula II

in which R¹, R², R^(2a) and R³ have the meanings indicated in Claim 1,and R denotes an indole-protecting group,and/or a base or acid of the formula I is converted into one of itssalts.

Above and below, the radicals R¹, R², R^(2a) and R³ have the meaningsindicated for the formula I, unless expressly indicated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methyl-butyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-tri-methylpropyl, further preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

One or two non-adjacent CH and/or CH₂ groups in A may also be replacedby N, O and/or S atoms and/or by —CH═CH— groups. A thus also denotes,for example, 2-methoxyethyl or 2-hydroxyethyl.

A furthermore preferably denotes unbranched or branched alkyl having1-6C atoms, in which one or two non-adjacent CH₂ groups may be replacedby an O, N and/or S atom and/or, in addition, 1-7H atoms may be replacedby F.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl,o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- orp-methylsulfonylphenyl, o-, m- or p-nitrophenyl, o-, m- orp-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- orp-dimethylaminophenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-methyl-aminosulfonylphenyl, o-, m- or p-aminocarbonylphenyl, o-, m- orp-carboxy-phenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-formylphenyl, o-, m- or p-cyanophenyl, further preferably 2,3-, 2,4-,2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes phenyl which is unsubstituted or mono- ordisubstituted by Hal and/or A.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Unsubstituted Het can thus also denote, for example, 2,3-dihydro-2-,-3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2-or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het furthermore preferably denotes a mono- or bicyclic aromatic,unsaturated or saturated heterocycle having 1 to 4 N, and/or O and/or Satoms which is unsubstituted or mono- or disubstituted by A.

Het very particularly preferably denotes furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl,indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl,1,3-benzodioxolyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl,tetrahydropyrazolyl, piperidinyl, morpholinyl, piperazinyl, oxazolidinylor isoxazolidinyl.

Het particularly preferably denotes azetidinyl, pyrrolidinyl,tetrahydroimidazolyl, tetrahydropyrazolyl, piperidinyl, morpholinyl,piperazinyl, oxazolidinyl or isoxazolidinyl.

Irrespective of further substitutions, Het′ preferably has the meaningsas indicated for Het.

Het′ furthermore preferably denotes a mono- or bicyclic aromaticheterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted ormay be mono- or disubstituted by A and/or [C(R³)₂]_(n)Het¹.

Het′ very particularly preferably denotes furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl,indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl or1,3-benzodioxolyl, each of which is unsubstituted or mono- ordisubstituted by A and/or [C(R³)₂]_(n)Het¹.

Het¹ preferably denotes a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be mono- or disubstituted by A.

Het¹ very particularly preferably denotes azetidinyl, pyrrolidinyl,tetrahydroimidazolyl, tetrahydropyrazolyl, piperidinyl, morpholinyl,piperazinyl, oxazolidinyl or isoxazolidinyl, each of which isunsubstituted or mono- or disubstituted by A.

R¹ preferably denotes —C(R³)(R⁴)—Ar.

R², R^(2a) preferably denote, in each case independently of one another,H or A.

R³ preferably denotes H, methyl, ethyl, propyl or butyl.

R⁴ preferably denotes H, —[C(R³)₂]_(m)N(R³)₂ or —[C(R³)₂]_(m)Het¹.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to II, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

in Ia R¹ denotes —C(R³)(R⁴)—Ar; in Ib R², R^(a) each, independently ofone another, denote H or A; in Ic R⁴ denotes H, —[C(R³)₂]_(m)N(R³)₂ or—[C(R³)₂]_(m)Het¹; in Id A denotes unbranched or branched alkyl having1-6 C atoms, in which one or two non-adjacent CH₂ groups may be replacedby an O, N and/or S atom and/or, in addition, 1-7 H atoms may bereplaced by F; in Ie Ar denotes phenyl which is unsubstituted or mono-or disubstituted by Hal and/or A; in If Het denotes azetidinyl,pyrrolidinyl, tetrahydroimidazolyl, tetra- hydropyrazolyl, piperidinyl,morpholinyl, piperazinyl, oxazolidinyl or isoxazolidinyl; in Ig Het′denotes a mono- or bicyclic aromatic heterocycle having 1 to 4 N, Oand/or S atoms, which is unsubstituted or may be mono- or disubstitutedby A and/or [C(R³)₂]_(n)Het¹; in Ih Het¹ denotes a monocyclic saturatedheterocycle having 1 to 2N and/or O atoms, which may be mono- ordisubstituted by A; in Ii Het denotes furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl,indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl,1,3-benzodioxolyl or azetidinyl, pyrrolidinyl, tetrahydroimidazolyl,tetrahydropyrazolyl, piperidinyl, morpholinyl, piperazinyl, oxazolidinylor isoxazolidinyl; in Ij Het′ denotes furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl,indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl or1,3-benzodioxolyl, each of which is unsubstituted or mono- ordisubstituted by A and/or [C(R³)₂]_(n)Het¹; in Ik Het¹ denotesazetidinyl, pyrrolidinyl, tetrahydroimidazolyl, tetra- hydropyrazolyl,piperidinyl, morpholinyl, piperazinyl, oxazolidinyl or isoxazolidinyl,each of which is unsubstituted or mono- or disubstituted by A; in Il R¹denotes —C(R³)(R⁴)—Ar, R², R^(2a) each, independently of one another,denote H or A, R³ denotes H or A, R⁴ denotes H, —[C(R³)₂]_(m)N(R³)₂ or—[C(R³)₂]_(m)Het¹; A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH₂ groups may be replaced by anO, N and/or S atom and/or, in addition, 1-7 H atoms may be replaced byF, Ar denotes phenyl which is unsubstituted or mono- or disubstituted byHal and/or A, Het¹ denotes a monocyclic saturated heterocycle having 1to 2N and/or O atoms, which may be once or twice by A, Hal denotes F,Cl, Br or I, m denotes 1 or 2,and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

Compounds of the formula I can preferably be obtained by cleaving theindole-protecting group off from compounds of the formula II.

The reaction is carried out in an inert solvent and is generally carriedout in the presence of an alkali or alkaline-earth metal hydroxide,carbonate or bicarbonate or another salt of a weak acid of the alkali oralkaline-earth metals, preferably of potassium, sodium, calcium orcaesium.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −15° and150°, normally between 10° and 100°, particularly preferably between 15°and 80° C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to alcohols, suchas, for example, methanol.

Preferred indole-protecting groups are, for example, sulfonyl-protectinggroups, such as tosyl or mesyl, furthermore protecting groups such as,for example, BOC.

Compounds of the formula II can preferably be obtained by reacting acompound of the formula III

-   -   in which    -   R², R^(2a) and R³ have the meanings indicated in Claim 1,    -   R denotes an indole-protecting group,    -   X denotes Cl, Br, I or OTf,        with trimethylacetylene and a transition-metal catalyst in a        Sonogashira reaction, preferably copper-catalysed [Lit.: Rafael        Chinchilla and Carmen Nájera, Chem. Rev. 2007, 107, 874-922] and        subsequently reacting with a compound of the formula IV        N═N═N—R¹  IV    -   in which R¹ has the meaning indicated in Claim 1, in an        azide-alkyne cycloaddition [Lit.: Morten Meldal and Christian        Wenzel Tornøe, Chem. Rev., 2008, 108 (8), 2952-3015].        Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline-earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogen-phosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline-earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline-earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active compound which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active compound compared withthe free form of the active compound or any other salt form of theactive compound used earlier. The pharmaceutically acceptable salt formof the active compound can also provide this active compound for thefirst time with a desired pharmacokinetic property which it did not haveearlier and can even have a positive influence on the pharmacodynamicsof this active compound with respect to its therapeutic efficacy in thebody.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active compound perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of active compoundper dosage unit. Preferred dosage unit formulations are those whichcomprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active compound. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active compound with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, can likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, tautomers and stereoisomersthereof can also be administered in the form of liposome deliverysystems, such as, for example, small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom various phospholipids, such as, for example, cholesterol,stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, tautomers andstereoisomers thereof can also be delivered using monoclonal antibodiesas individual carriers to which the compound molecules are coupled. Thecompounds can also be coupled to soluble polymers as targeted medicamentcarriers. Such polymers may encompass polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsiloncaprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block co-polymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active compoundcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activecompound can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active compound can be formulated to givea cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active compound is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, and atleast one further medicament active compound.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable salts and stereoisomers thereof, including    mixtures thereof in all ratios,    -   and-   (b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active compound indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active compoundsfor mammals, especially for humans, in the treatment and control ofcancer diseases.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts, tautomers andstereoisomers thereof for the preparation of a medicament for thetreatment or prevention of cancer. Preferred carcinomas for thetreatment originate from the group cerebral carcinoma, urogenital tractcarcinoma, carcinoma of the lymphatic system, stomach carcinoma,laryngeal carcinoma and lung carcinoma bowel cancer. A further group ofpreferred forms of cancer are monocytic leukaemia, lung adenocarcinoma,small-cell lung carcinomas, pancreatic cancer, glioblastomas and breastcarcinoma.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts, tautomers and stereoisomers thereoffor the preparation of a medicament for the treatment and/or control ofa tumour-induced disease in a mammal, in which to this method atherapeutically effective amount of a compound according to theinvention is administered to a sick mammal in need of such treatment.The therapeutic amount varies according to the particular disease andcan be determined by the person skilled in the art without undue effort.

Particular preference is given to the use for the treatment of adisease, where the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thesquamous epithelium, the bladder, the stomach, the kidneys, of head andneck, the oesophagus, the cervix, the thyroid, the intestine, the liver,the brain, the prostate, the urogenital tract, the lymphatic system, thestomach, the larynx and/or the lung.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The invention furthermore relates to the use of the compounds accordingto the invention for the treatment of bone pathologies, where the bonepathology originates from the group osteosarcoma, osteoarthritis andrickets.

The compounds of the formula I may also be administered at the same timeas other well-known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated.

The present compounds are also suitable for combination with knownanti-cancer agents. These known anti-cancer agents include thefollowing: oestrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors, HIV protease inhibitors, reverse transcriptase inhibitorsand further angiogenesis inhibitors. The present compounds areparticularly suitable for administration at the same time asradiotherapy. “Oestrogen receptor modulators” refers to compounds whichinterfere with or inhibit the binding of oestrogen to the receptor,regardless of mechanism. Examples of oestrogen receptor modulatorsinclude, but are not limited to, tamoxifen, raloxifene, idoxifene,LY353381, LY 117081, toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.

“Androgen receptor modulators” refers to compounds which interfere withor inhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere withor inhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.“Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosylate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)platinum, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)bis-mu-(hexane-1,6-diamine)-mu-[diamineplatinum(II)]bis-[diamine(chloro)platinum(II)]tetrachloride,diarisidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidenechartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin,BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide,sobuzoxane, 2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-amino-ethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

“Antiproliferative agents” include antisense RNA and

-oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-dichloro-phenyl)urea,N6-[4-deoxy-4-[N2-[2

,4

-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannoheptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also include monoclonal antibodies to growth factors other thanthose listed under “angiogenesis inhibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

Evidence of the Action of Pharmacological Inhibitors on theProliferation/Vitality of Tumour Cells In Vitro

1.0 Background

In the present experiment description, the inhibition of tumour cellproliferation/tumour cell vitality by active compounds is described.

The cells are sown in a suitable cell density in microtitre plates(96-well format) and the test substances are added in the form of aconcentration series. After four further days of cultivation inserum-containing medium, the tumour cell proliferation/tumour cellvitality can be determined by means of an Alamar Blue test system.

2.0 Experimental Procedure

2.1 Cell Culture

For example commercially available colon carcinoma cell lines, ovarycell lines, prostate cell lines or breast cell lines, etc.

The cells are cultivated in medium. At intervals of several days, thecells are detached from the culture dishes with the aid of trypsinsolution and sown in suitable dilution in fresh medium. The cells arecultivated at 37° Celsius and 10% CO₂.

2.2. Sowing of the Cells

A defined number of cells (for example 2000 cells) per culture/well in avolume of 180 μl of culture medium are sown in microtitre plates (96well cell-culture plates) using a multichannel pipette. The cells aresubsequently cultivated in a CO2 incubator (37° C. and 10% CO2).

2.3. Addition of the Test Substances

The test substances are dissolved, for example, in DMSO and subsequentlyemployed in corresponding concentration (if desired in a dilutionseries) in the cell culture medium. The dilution steps can be adapteddepending on the efficiency of the active compounds and the desiredspread of the concentrations. Cell culture medium is added to the testsubstances in corresponding concentrations. The addition of the testsubstances to the cells can take place on the same day as the sowing ofthe cells. To this end, in each case 20 μl of substance solution fromthe predilution plate are added to the cultures/wells. The cells arecultivated for a further 4 days at 37° Celsius and 10% CO₂.

2.4. Measurement of the Colour Reaction

In each case, 20 μl of Alamar Blue reagent are added per well, and themicrotitre plates are incubated, for example, for a further seven hoursin a CO2 incubator (at 37° C. and 10% CO2). The plates are measured in areader with a fluorescence filter at a wavelength of 540 nm. The platescan be shaken gently immediately before the measurement.

3. Evaluation

The absorbance value of the medium control (no cells and test substancesused) is subtracted from all other absorbance values. The controls(cells without test substance) are set equal to 100 percent, and allother absorbance values are set in relation thereto (for example in % ofcontrol):

Calculation:

$\frac{\begin{matrix}{100*\left( {{{value}\mspace{14mu}{with}\mspace{14mu}{cells}\mspace{14mu}{and}\mspace{14mu}{test}\mspace{14mu}{substance}} -} \right.} \\\left. {{value}\mspace{14mu}{of}\mspace{14mu}{medium}\mspace{14mu}{control}} \right)\end{matrix}}{\left( {{{value}\mspace{14mu}{with}\mspace{14mu}{cells}} - {{value}\mspace{14mu}{of}\mspace{14mu}{medium}\mspace{14mu}{control}}} \right)}$

IC₅₀ values (50% inhibition) are determined with the aid of statisticsprograms, such as, for example, RS1.

IC₅₀ data of compounds according to the invention are indicated in Table1.

4.0 Test for the Inhibition of PDK1

The experimental batches are carried out in a flashplate system with 384wells/microtitration plate.

In each case, the PDK1 sample His₆-PDK1(1-50)(3.4 nM), the PDK1substrate biotin-bA-bA-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (400 nM),4 μM ATP (with 0.2 μCi of ³³P-ATP/well) and the test substance in 50 μlof conventional experimental solution per well are incubated at 30° C.for 60 min. The test substances are employed in correspondingconcentrations (if desired in a dilution series). The control is carriedout without test substance. The reaction is stopped using standardmethods and washed. The activity of the kinase is measured via theincorporated radioactivity in top count. In order to determine thenon-specific kinase reaction (blank value), the experimental batches arecarried out in the presence of 100 nM staurosporine.

5.0 Evaluation

The radioactivity (decompositions per minute) of the blank value (no useof test substance in the presence of staurosporine) is subtracted fromall other radioactivity values. The controls (kinase activity withouttest substance) are set equal to 100 percent and all other radioactivityvalues (after subtracting the blank value) are expressed set in relationthereto (for example in % of the control).

Calculation:

$\frac{100*\begin{matrix}\left( {{{value}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{kinase}\mspace{14mu}{activity}\mspace{14mu}{with}\mspace{14mu}{test}\mspace{14mu}{substance}} -} \right. \\\left. {{blank}\mspace{14mu}{value}} \right)\end{matrix}}{\left( {{{value}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{control}} - {{blank}\mspace{14mu}{value}}} \right)} = {\%\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{control}}$

IC₅₀ values (50% inhibition) are determined with the aid of statisticsprogrammes, such as, for example, RS1. IC₅₀ data of compounds accordingto the invention are indicated in Table 1.

Material Order No. Manufacturer Microtitre plates for cell culture 167008 Nunc (Nunclon Surface 96-well plate) DMEM P04-03550 Pan BiotechPBS (10x) Dulbecco 14200-067 Gibco 96-well plates (polypropylene) 267334 Nunc AlamarBlue ™ BUF012B Serotec FCS   1302 Pan Biotech GmbHTrypsin/EDTA solution 10x L 2153 Biochrom AG 75 cm² culture bottles 353136 BD Falcon A2780 93112519 ECACC Colo205 CCL222 ATCC MCF7 HTB22ATCC PC3 CRL-1435 ATCC 384-well flash plates SMP410A001PK Perkin ElmerIKK—Kinase Test (IKKepsilon)

The kinase assay is performed as 384-well flashplate assay.

1 nM IKK, 800 nM biotinylated I B (19-42) peptide(biotin-C6-C6-GLKKERLLDDRHDSGLDSMKDEE) and 10 μM ATP (with 0.3 μCi of³³P-ATP/well) are incubated in a total volume of 50 μl (10 mM MOPS, 10mM magnesium acetate, 0.1 mM EGTA, 1 mM dithiothreitol, 0.02% of Brij35,0.1% of BSA, 0.1% of BioStab, pH 7.5) with or without test substance at30° C. for 120 min. The reaction is stopped using 25 μl of 200 mM EDTAsolution, filtered off with suction after 30 min at room temperature,and the wells are washed 3 times with 100 μl of 0.9% NaCl solution. Thenon-specific proportion of the kinase reaction (blank) is determinedusing 3 μM BX-795. Radioactivity is measured in the Topcount. IC₅₀values are calculated using RS1.

TBK1—Kinase Test

The kinase assay is performed as 384-well flashplate assay. 0.6 nM TANKbinding kinase (TBK1), 800 nM biotinylated MELK-derived peptide(biotin-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR) and 10 μM ATP (with 0.25 μCi of³³P-ATP/well) are incubated in a total volume of 50 μl (10 mM MOPS, 10mM magnesium acetate, 0.1 mM EGTA, 1 mM DTT, 0.02% of Brij35, 0.1% ofBSA, pH 7.5) with or without test substance at 30° C. for 120 min. Thereaction is stopped using 25 μl of 200 mM EDTA solution, filtered offwith suction after 30 min at room temperature, and the wells are washed3 times with 100 μl of 0.9% NaCl solution. The non-specific proportionof the kinase reaction (blank) is determined using 100 nM staurosporine.Radioactivity is measured in the Topcount. IC₅₀ values are calculatedusing RS1.

HPLC/MS Method:

Column: Chromolith SpeedROD RP-18e, 50×4.6 mm²

Gradient: A:B=96:4 to 0:100

Flow rate: 2.4 ml/min

Eluent A: water+0.05% of formic acid

Eluent B: acetonitrile+0.04% of formic acid

Wavelength: 220 nm

Mass spectroscopy: positive mode

Example 1 Preparation of5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine(“A1”)

1.1 A suspension of 1.00 g (6.32 mmol) of4-chloro-7H-pyrrolo[2,3-d]-pyrimidine and 5.20 g (15.8 mmol) of caesiumcarbonate in 30 ml of 2-methoxy-ethanol is heated under reflux for 24hours. The reaction mixture is adsorbed onto kieselguhr andchromatographed on a silica-gel column withdichloromethane/methanol/aqueous ammonia (100:1:1) as eluent, giving4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine as colourless crystals;m.p. 137-139° C.;

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=3.30 (d, J=0.9 Hz, 3H), 3.70-3.73 (m,2H), 4.57-4.61 (m, 2H), 6.46-6.48 (m, 1H), 7.33-7.36 (m, 1H), 8.35 (d,J=0.6 Hz, 1H), 12.0 (bs, 1H).

1.2 A solution of 1.28 g (5.05 mmol) of iodine in 10 ml of DMF is addeddropwise to a mixture of 966 mg (5.00 mmol) of4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine and 825 mg (12.5 mmol)of solid potassium hydroxide in 10 ml of DMF, and the mixture issubsequently stirred at room temperature for 50 minutes. The reactionmixture is poured into 100 ml of ice-water (containing 0.5% by weight ofammonia and 0.1% by weight of sodium disulfite) and left at 5° C. for 15minutes. The precipitate formed is filtered off with suction, washedwith 100 ml of ice-water and dried in vacuo:5-iodo-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine as yellow solid.

1.3 49 mg (0.40 mmol) of 4-dimethylaminopyridine are added to asuspension of 1.33 g (4.15 mmol) of5-iodo-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine in 8 ml ofdichloromethane, and a solution of 1.33 g (5.93 mmol) of di-tert-butyldicarbonate in 8 ml of dichloromethane is then added dropwise over thecourse of 20 minutes. The mixture is stirred at room temperature for 30minutes, washed with 85 ml of 0.1 N aqueous hydrochloric acid, and theaqueous phase is extracted twice with dichloromethane. The combinedorganic phases are dried over sodium sulfate and evaporated. The residueis chromatographed on a silica-gel column with petroleum ether/ethylacetate as eluent: tert-butyl5-iodo-4-(2-methoxyethoxy)pyrrolo[2,3-d]pyrimidine-7-carboxylate aspale-yellow oil;

¹H-NMR (500 MHz, CDCl₃): δ [ppm]=1.67 (s, 9H), 3.49 (s, 3H), 3.84-3.88(m, 2H), 4.67-4.71 (m, 2H), 7.62 (s, 1H), 8.62 (s, 1H).

1.4 0.37 ml (2.58 mmol) of trimethylsilylacetylene and 0.48 ml (3.44mmol) of triethylamine are added successively to a suspension, keptunder argon, of 24 mg (0.03 mmol) of bis(triphenylphosphine)palladiumdichloride, 13 mg (0.07 mmol) of copper(I) iodide and 720 mg (1.72 mmol)of tert-butyl5-iodo-4-(2-methoxyethoxy)-pyrrolo[2,3-d]pyrimidine-7-carboxylate in 9ml of THF, and the mixture is stirred at room temperature for one hourunder argon. 2.58 ml (2.58 mmol) of a 1 M solution of tetrabutylammoniumfluoride in THF are then added, and the reaction mixture is stirred atroom temperature for 30 minutes. A solution of 234 mg (1.782 mmol) ofbenzyl azide in 9 ml of methanol is then added, and the reaction mixtureis stirred at room temperature for 87 hours. The reaction mixture isadsorbed onto kieselguhr and chromatographed on a silica-gel column withpetroleum ether/ethyl acetate 1:1 as eluent: tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxyethoxy)-pyrrolo[2,3-d]pyrimidine-7-carboxylateas pale-yellow foam.

1.5 195 mg (1.40 mmol) of potassium carbonate are added to a solution of197 mg (0.56 mmol) of tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxy-ethoxy)pyrrolo[2,3-d]pyrimidine-7-carboxylatein 2.8 ml of methanol, and the mixture is stirred at room temperaturefor 1 hour. The reaction mixture is adsorbed onto kieselguhr andchromatographed on a silica-gel column withdichloromethane/methanol/ammonia water as eluent:5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine(“A1”) as colourless crystals; m.p. 240° C.;

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=3.23 (s, 3H), 3.68-3.71 (m, 2H),4.57-4.60 (m, 2H), 5.65 (s, 2H), 7.29-7.36 (m, 3H), 7.37-7.42 (m, 2H),7.85 (s, 1H), 8.37 (s, 1H), 8.43 (s, 1H), 12.3 (bs, 1H).

The following compounds are obtained analogously

No. Name/structure   “A2”

HPLC/MS Rt. 1.86 min; HPLC/MS 307 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 12.25 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.38 (m,5H), 5.67 (s, 2H), 4.05 (s, 3H) “A3”

“A4”

“A5”

Example 2 Preparation of5-(1-benzyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (“A6”)

2.1 10 ml (7.1 mmol) of triethylamine and 379 mg (3.10 mmol) of4-(dimethylamino)pyridine are added successively to a suspension of 7.60g (31.0 mmol) of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (synthesis describedin WO 2009/080682) in 200 ml of dichloromethane. A solution of 7.30 ml(34.0 mmol) of di-tert-butyl dicarbonate in 200 ml of dichloromethane isadded dropwise thereto at room temperature with stirring. After stirringat room temperature for one hour, the reaction mixture is extractedthree times with water. The organic phase is dried over sodium sulfateand evaporated, giving tert-butyl5-iodopyrrolo[2,3-d]pyrimidine-7-carboxylate as yellow solid; HPLC/MS:2.26 min, [M+H] 346.

2.2 361 μl (2.61 mmol) of trimethylsilylacetylene and 402 μl (2.90 mmol)of triethylamine were added to a suspension, kept under nitrogen, of 500mg (1.45 mmol) of tert-butyl5-iodopyrrolo[2,3-d]pyrimidine-7-carboxylate, 19.5 mg (0.028 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 11.2 mg (0.059 mmol)of copper(I) iodide in 5 ml of THF, and the mixture was stirred at roomtemperature for 18 hours. Nitrogen was then passed through the reactionmixture for 10 minutes, and 4.4 ml of a 1 M solution oftetrabutylammonium fluoride in THF were subsequently added. Afterstirring at room temperature for three hours, 309 mg (2.32 mmol) ofbenzyl azide were added, and the reaction mixture was stirred at roomtemperature for 40 hours under nitrogen. The reaction mixture waspartitioned between water and ethyl acetate. The organic phase was driedover sodium sulfate and evaporated. The residue was purified bypreparative HPLC, giving tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,3-d]pyrimidine-7-carboxylateas colourless solid; HPLC/MS: 2.23 min, [M+H] 377.

17 mg (0.13 mmol) of potassium carbonate were added to a solution of 13mg (0.035 mmol) of tert-butyl5-(1-benzyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,3-d]pyrimidine-7-carboxylatein 10 ml of methanol, and the mixture was stirred at room temperaturefor 18 hours. The reaction mixture was evaporated, and the residue waspurified by preparative HPLC, giving5-(1-benzyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine ascolourless solid; HPLC/MS: 1.48 min, [M+H] 277;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 12.31 (s, 1H), 9.44 (s, 1H), 8.81 (s,1H), 8.59 (s, 1H), 7.98 (d, J=2.5, 1H), 7.38 (m, 5H), 5.66 (s, 2H).

“A7” and “A8” are prepared analogously, starting from5-iodo-2-methoxy-7H-pyrrolo[2,3-d]pyrimidine and5-iodo-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine respectively (bothcommercially available).

No. Name/structure   “A7”

“A8”

Example 3 Synthesis of 1-(3-azido-3-phenylpropyl)azetidine (for thepreparation of “A5”)

3.1 1.85 ml of triethylamine and 440 μl (6.55 mmol) of azetidine areadded to a solution of 1.00 g (5.93 mmol) of3-chloro-1-phenylpropan-1-one in ethanol, and the mixture is stirred atRT for 4 hours. The reaction mixture is partitioned between water andsaturated sodium chloride solution. The organic phase is dried oversodium sulfate and evaporated: 3-azetidin-1-yl-1-phenyl-propan-1-one ascolourless oil; HPLC/MS 0.7 min; [M+H] 190.

3.2 1.60 g (42.3 mmol) of sodium borohydride are added in portions to asolution, kept at 0° C., of 2.76 g (13.7 mmol) of3-azetidin-1-yl-1-phenylpropan-1-one in 50 ml of methanol), and themixture is stirred at RT for 3 h. Water is added, the methanol isremoved in vacuo, and the residue is taken up using ethyl acetate. Themixture is washed three times with water and once with saturated sodiumchloride solution, dried over sodium sulfate and evaporated:3-azetidin-1-yl-1-phenylpropan-1-ol as viscous oil; HPLC/MS 0.7 min;[M+H] 192.

3.3 A solution of 1.12 ml (14.30 mmol) of methanesulfonyl chloride in 5ml of dichloromethane is added dropwise to a solution of 2.49 g (13.0mmol) of 3-azetidin-1-yl-1-phenylpropan-1-ol and 2.70 ml (19.5 mmol) oftriethylamine in 65 ml of dichloromethane, and the reaction mixture isstirred at room temperature for 3 hours. The reaction mixture is washedthree times with water, dried over sodium sulfate and evaporated todryness: 3-azetidin-1-yl-1-phenylpropyl methanesulfonate as viscous oil,which was employed for the following reaction without furtherpurification.

3.4 1.50 g (23.1 mmol) of sodium azide are added to a solution of 2.00 g(7.43 mmol) of 3-azetidin-1-yl-1-phenylpropyl methanesulfonate in 50 mlof DMF, and the mixture is stirred at room temperature for 48 hours. Thereaction mixture is partitioned between water and ethyl acetate. Theorganic phase is dried over sodium sulfate, evaporated, and the residueis chromatographed on a silica-gel column with ethyl acetate/methanol aseluent: 1-(3-azido-3-phenyl-propyl)azetidine as colourless viscous oil;HPLC/MS 0.9 min; [M+H] 217.

The azide derivative required for “A4” is prepared analogously.

Example 4 Synthesis of5-{1-[1-(2,3-difluorophenyl)-3-piperidin-1-ylpropyl]-1H-1,2,3-triazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine(“A9”)

The preparation is carried out analogously to Example 1; the aziderequired for this purpose is prepared analogously to Example 3; “A9” isobtained as trifluoroacetate.

HPLC/MS Rt. 1.27 min;

HPLC/MS 424 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 12.6 (s, 1H), 9.49 (s, 1H), 9.20 (s,1H), 8.90 (s, 1H), 8.72 (s, 1H), 8.07 (d, J=2.3, 1H), 7.51 (ddd, J=18.1,7.7, 2.3, 1H), 7.33 (m, 2H), 6.27 (dd, J=8.7, 5.8, 1H), 3.20 (m, 2H),2.98 (m, 4H), 2.70 (m, 2H), 1.80 (m, 2H), 1.64 (m, 3H), 1.38 (m, 1H).

Inhibition of PDK1, TBK1 and IKK

IC₅₀ of compounds according to the invention

Compound No. IC₅₀ PDK1 IC₅₀ TBK1 IC₅₀ IKK “A1” A A B “A2” A A A “A3”“A6” B B B “A9” B C B IC₅₀ : 10 nM-1M = A 1M-10M = B >10M = CVitality Assay

IC₅₀ of compounds according to the invention

Compound No. IC₅₀ A2780 IC₅₀ HCT 116 “A1” B B IC₅₀ : 10 nM-1M = A 1M-10M= B

The following examples relate to medicaments:

Example A Injection Vials

A solution of 100 g of an active compound of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activecompound.

Example B Suppositories

A mixture of 20 g of an active compound of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of active compound.

Example C Solution

A solution is prepared from 1 g of an active compound of the formula I,9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis pressed in a conventional manner to give tablets in such a way thateach tablet contains 10 mg of active compound.

Example F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of active compound of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active compound.

Example H Ampoules

A solution of 1 kg of active compound of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active compound.

The invention claimed is:
 1. A compound of the formula I

in which R¹ denotes A, —C(R³)(R⁴)—Ar, —C(R³)(R⁴)-Het or —C(R³)(R⁴)-Cyc,R², R^(2a) each, independently of one another, denote H, A, Hal, CN,—[C(R³)₂]_(n)—Ar′, —[C(R³)₂]_(n)-Het′, —[C(R³)₂]_(n)-Cyc, OR³ or N(R³)₂,R³ denotes H, R⁴ denotes H, A, —[C(R³)₂]_(m)OR³, —[C(R³)₂]_(m)N(R³)₂ or—[C(R³)₂]_(m)Het¹, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH₂ groups may be replaced by O,N and/or S atoms and/or by —CH═CH— groups and/or, in addition, 1-7 Hatoms may be replaced by F, Cyc denotes cycloalkyl having 3, 4, 5, 6 or7 C atoms, Ar denotes phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA,NR³SO₂A, COR³, SO₂N(R³)₂ and/or S(O)_(n)A, Ar′ denotes phenyl which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OR³, N(R³)₂,SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A,CO-Het¹, Het¹, [C(R³)₂]_(n)N(R³)₂, [C(R³)₂]_(n)Het¹,O[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹, NHCOOA, NHCON(R³)₂,NHCOO[C(R³)₂]_(n)N(R³)₂, NHCOO[C(R³)₂]_(n)Het¹,NHCONH[C(R³)₂]_(n)N(R³)₂, NHCONH[C(R³)₂]₁Het¹, OCONH[C(R³)₂]_(n)N(R³)₂,OCONH[C(R³)₂]_(n)Het¹, CO-Het¹, CHO and/or COA, Het denotes a mono- orbicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N,and/or O and/or S atoms which is unsubstituted or mono- or disubstitutedby Hal, A, OR³, N(R³)₂, NO₂, CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A, COR³,SO₂NR³ and/or S(O)_(n)A, Het′ denotes a mono-, bi- or tricyclicsaturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, which is unsubstituted or may be mono- or disubstituted by Hal,A, OR³, N(R³)₂, SR³, NO₂, CN, COOR³, CON(R³)₂, NR³COA, NR³SO₂A,SO₂N(R³)₂, S(O)_(m)A, CO-Het¹, Het¹, [C(R³)₂]_(n)N(R³)₂,[C(R³)₂]_(n)Het¹, O[C(R³)₂]_(n)N(R³)₂, O[C(R³)₂]_(n)Het¹, NHCOOA,NHCON(R³)₂, NHCOO[C(R³)₂]_(n)N(R³)₂, NHCOO[C(R³)₂]_(n)Het¹,NHCONH[C(R³)₂]₁N(R³)₂, NHCONH[C(R³)₂]_(n)Het¹, OCONH[C(R³)₂]_(n)N(R³)₂,OCONH[C(R³)₂]_(n)-Het¹, CO-Het¹, CHO, COA, ═S, ═NH, =NA and/or ═O(carbonyl oxygen), Het¹ denotes a monocyclic saturated heterocyclehaving 1 to 2 N and/or O atoms, which may be mono- or disubstituted byA, OA, OH, Hal and/or ═O (carbonyl oxygen), Hal denotes F, Cl, Br or I Ndenotes 0, 1 or 2 m denotes 1 or 2, or a pharmaceutically usable salt,tautomer or stereoisomer thereof, including mixtures thereof in allratios.
 2. A compound according to claim 1 in which R¹ denotes—C(R³)(R⁴)—Ar, or a pharmaceutically usable salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios.
 3. Acompound according to claim 1 in which R², R^(2a) each, independently ofone another, denotes H or A, or a pharmaceutically usable salt, tautomeror stereoisomer thereof, including mixtures thereof in all ratios.
 4. Acompound according to claim 1 in which R⁴ denotes H, —[C(R³)₂]_(m)N(R³)₂or —[C(R³)₂]_(m)Het¹, or a pharmaceutically usable salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios.
 5. Acompound according to claim 1 in which A denotes unbranched or branchedalkyl having 1-6 C atoms, in which one or two non-adjacent CH₂ groupsmay be replaced by an O, N and/or S atom and/or, in addition, 1-7 Hatoms may be replaced by F, or a pharmaceutically usable salt, tautomeror stereoisomer thereof, including mixtures thereof in all ratios.
 6. Acompound according to claim 1 in which Ar denotes phenyl which isunsubstituted or mono- or disubstituted by Hal and/or A, or apharmaceutically usable salt, tautomer or stereoisomer thereof,including mixtures thereof in all ratios.
 7. A compound according toclaim 1 in which Het¹ denotes a monocyclic saturated heterocycle having1 to 2 N and/or O atoms, which may be mono- or disubstituted by A, or apharmaceutically usable salt, tautomer or stereoisomer thereof,including mixtures thereof in all ratios.
 8. A compound according toclaim 1 in which Het¹ denotes azetidinyl, pyrrolidinyl,tetrahydroimidazolyl, tetrahydropyrazolyl, piperidinyl, morpholinyl,piperazinyl, oxazolidinyl or isoxazolidinyl, each of which isunsubstituted or mono- or disubstituted by A, or a pharmaceuticallyusable salt, tautomer or stereoisomer thereof, including mixturesthereof in all ratios.
 9. A compound according to claim 1 in which R¹denotes —C(R³)(R⁴)—Ar, R², R^(2a) each, independently of one another,denote H or A, R³ denotes H, R⁴ denotes H, —[C(R³)₂]_(m)N(R³)₂ or—[C(R³)₂]_(m)Het¹, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH₂ groups may be replaced by anO, N and/or S atom and/or, in addition, 1-7 H atoms may be replaced byF, Ar denotes phenyl which is unsubstituted or mono- or disubstituted byHal and/or A, Het¹ denotes a monocyclic saturated heterocycle having 1to 2 N and/or O atoms, which may be once or twice by A, Hal denotes F,Cl, Br or I, M denotes 1 or 2, or a pharmaceutically usable salt,tautomer or stereoisomer thereof, including mixtures thereof in allratios.
 10. A compound according to claim 1, selected from the followingcompounds: Compound No. Name and/or structure “A1”5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine “A2”5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine “A3”5-[1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidine “A4”(3-{4-[4-(2-Methoxyethoxy)-7H-pyrrolo[2,3-d]-pyrimidin-5-yl]-1,2,3-triazol-1-yl}-3-phenylpropyl)- dimethylamine “A5”5-[1-(3-Azetidin-1-yl-1-phenylpropyl)-1H-1,2,3-triazol-4-yl]-4-(2-methoxyethoxy)-7H-pyrrolo[2-3-d]- pyrimidine “A6”5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]- pyrimidine “A7”5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-methoxy-7H-pyrrolo[2,3-d]pyrimidine “A8”5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine “A9”5-{1-[1-(2,3-Difluorophenyl)-3-piperidin-1-yl-propyl]-1H-1,2,3-triazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine

or a pharmaceutically usable salt, tautomer or stereoisomer thereof,including mixtures thereof in all ratios.
 11. A process for thepreparation of a compound of the formula I according to claim 1 or apharmaceutically usable salt, tautomer or stereoisomer thereof,comprising: cleaving off an indole-protecting group from a compound ofthe formula II

in which R¹, R², R^(2a) and R³ have the meanings indicated in claim 1and R denotes the indole-protecting group, and/or converting a base oracid of the formula I into one of its salts.
 12. A medicamentcomposition comprising ing at least one compound of the formula Iaccording to claim 1 or a pharmaceutically usable salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.
 13. A method for inhibitingPDK-1 in vitro, which comprises contacting a compound according to claim1 or a pharmaceutically usable salt, tautomer or stereoisomer thereof,including mixtures thereof in all ratios, with PDK-1.